This project aims to identify abnormalities in brain function that contribute to dependence on drugs, and to offer leads in developing new treatment modalities. Our strategies have included evaluating the relationship between cocaine craving and brain metabolism as measured using the [F-18]flurodeoxyglucose-positron emission tomography (PET) method and electroencephalographic (EEG) signs of arousal; comparing differences in the size of brain structures as they relate to substance abusers; and determining the cognitive effects of nicotine on brain function. A high-resolution magnetic resonance imaging study, measuring prefrontal lobe volumes in 25 polysubstance abusers and 14 normal volunteers, found that the total volume of the prefrontal lobe was significantly smaller in substance abusers. This deficit was subsequently characterized as a reduction in the volume of gray but not white matter. These results indicate that hypoplasia and/or atrophy in the prefrontal lobe accompanies polysubstance abuse and were the basis for a study of prefrontal cortical function. The structural deficit in prefrontal volume may be related to the poor performance of drug abusers on a task that is sensitive to orbitofrontal damage in humans. This task (Gambling Task) requires that the subject balance short term gains against long term losses. Polydrug abusers (n=30) performed significantly more poorly on this task than controls (n =24). On the other hand, there was no difference between polydrug abusers and controls on the Wisconsin Card Sorting Task, a standard neuropsychological test of frontal cortical function, which is sensitive to damage of the dorsolateral prefrontal cortex. These data imply that polydrug abuse may be associated with functional deficits in specific portions of the prefrontal cortex. A new study is evaluating the effects of nicotine on brain function, as measured by PET with [O-15]H2O. Regional cerebral blood flow activation during a working memory task was assessed in 12 abstinent (12 h) nicotine-dependent smokers and 12 non-dependent controls. In nicotine-dependent smokers, memory performance seemed to be mediated by different neural substrates than those in controls, suggesting that chronic exposure to nicotine alters cognitive strategies or neural systems subserving memory. Regional activation during performance of a working memory task (N-Back test) was increased by nicotine in controls, but not in smokers.